Process for the preparation of 4-chloro-2-hydroxybenzothiazole

ABSTRACT

A process is described for the production of 4-chloro-2hydroxybenzothiazole (which is an intermediate in the production of benazolin) by diazotisation of the corresponding 2-amino hydrohalide followed by hydrolysis, in which the diazotisation is conducted in the presence of a halogenated aliphatic hydrocarbon solvent.

United States Patent [191 Lowe [ June 10, 1975 PROCESS FOR THE PREPARATION OF 4-CHLORO-2-HYDROXYBENZOTHIAZOLE [75] Inventor: James L. Lowe, Nottingham,

England [73] Assignee: The Boots Co., Ltd., Nottingham,

England [22] Filed: Nov. 23, 1973 21 Appl. NO.Z 418,733

[30] Foreign Application Priority Data Dec. 1, 1972 United Kingdom 55684/72 [52] US. Cl. 260/304 [51] Int. Cl C07d 91/44 [58] Field of Search 260/304 Primary ExaminerR. Gallagher Attorney, Agent, or FirmHammond & Littell [5 7 ABSTRACT 7 Claims, N0 Drawings IMPROVED PROCESS FOR THE PREPARATION OF 4-CHLORO-Z-HYDROXYBENZOTHIAZOLE The compound 4rchloro-2 oxobenzothiazolin-3- ylacetic acid (often referred to as 'benazolin) and esters and salts thereof are used Widely as herbicides. Typical saltsare alkali metal salts, for example sodium or, preferably, potassium. salts and amine salts for example triethylamine or diethanolamine or. preferably, dimethylamine salts. Typical esters are C, alkyl esters for example methyl, isopropyl or, preferably, ethyl esters. Benazolin and its esters and salts was originally described in British Pat. Specification No. 862,226. The

had been described in a paper by Elderfield and Short (:J Gr'g. Chem. l953 18 1092) as being prepared by a process; involving diazotisation of 2-amino-4- chlorobenzothiazole in a mixture of bromine and hydrobromic acid to give 2-bromo-4- chlorobenzothiazole, followed by hydrolysis of this to give the required product. The yields obtained were 72% for the first stage and 77% for the second, making an overall yield of 56% for the synthesis of 4-chloro-2- hydroxybenzothiazole from 2-amino-4- chlorobenzothiazole. The process was not very satisfactory for commercial production.

In British Pat. Specification No. 966,496 processes were described by which 2-amino-4- chlorobenzothiazole could be converted to 2,4- dichlorobenzothiazole in high yield and this in turn could be converted to 4-chloro-2 hydroxybenzothiazole in high yield giving a fairly satis factory overall yield for the entire reaction of at least 80%. The process comprised diazotising 2-amino-4- chlorobenzothiazole in hydrochloric acid followed by hydrolysing the dichloro compound. It was described that the reaction could be facilitated by the presence of a water miscible solvent and that particularly desirable conditions are obtained if benzene or toluene is included, benzene giving the most satisfactory results. The duration of the diazotisation was long, e.g. above 16 hours.

A modification of this process has been used com mercially on a large scale. In this modified process Z-aminc-4-chlorobenzothiazole hydrobromide is converted to a mixture of 2,4-dichlorobenzothiazole and 2-bromo-4chlorobenzothiazole and the mixture hydrolysed to give 4-chloro-Z-hydroxybenzothiazole. Overall yields of, say, 70 80%, such as are obtained by this process, are much better than the prior yields of 56% but the process still leaves much to be desired commercially. Thus long reaction times are needed to achieve these yields. Also, the 4-chloro-2- hydroxybenzothiazole is contaminated with significant amounts of unacceptable by-products that have to be removed, generally at a later stage in the overall process for making benazolin or its esters or salts. This involves an extra purification step which is clearly timeconsuming and costly and which it would be desirable to avoid. Further, the formation of these unwanted byproducts represent a waste of starting material.

The purpose of the invention has therefore been to devise a method of making 4-chloro-2- hydroxybenzothiazole in a higher degree of purity and in better yield and/or shorter reaction time than has been obtainable previously on a commercial scale as an intermediate in the preparation of benazolin and its esters and salts.

It has now surprisingly been found that improved purity and improved yield and/or shorter reaction time can in fact be obtained by the use of particular water immiscible solvents for the diazotisation. Thus it is now possible to make benazolin and its esters and salts to such a high degree of purity that any impurities that are present are in such small amounts and are such that it is no longer essential to conduct the above mentioned purification step. Also it is now possible to obtain yields that, in the same reaction times as were used in the prior processes, are better than were obtainable previously or to obtain satisfactory yields in much shorter reaction times than could be used previously to obtain satisfactory yields, and/or reduce the wastage in starting material.

According to the invention a process for preparing 4-chloro-2-hydroxybenzothiazole comprises diazotising 2-amino-4-chlorbenzothiazole hydrolhalide and hydrolysing the product, the diazotisation being carried out in the presence of a halogenated aliphatic hydrocarbon in which the major products of the diazotisation reaction are soluble to the extent of at least 10% w/v at 20C.

The major product of the diazotisation reaction are 2-halo-4-chlorobenzothiazoles. When the 2-amino-4- chlorobenzothiazole is in the preferred form of the hydrobromide, the major product is 2-bromo-4- chlorobenzothiazole. 2,4-Dichlorobenzothiazole is also usually formed.

Preferred halogenated aliphatic hydrocarbons for use in the invention are chlorinated hydrocarbons, for example ethylene dichloride which is particularly preferred, methylene chloride, chloroform, carbon tetrachloride, tetrachlorethane, trichloroethylene, perchloroethylene, 1,2-dichloropropane and 1,1 ,1- trichloroethane. Other halogenated hydrocarbons include bromine-containing hydrocarbons, for example ethylene dibromide. It is preferred that the solvent is one which has a boiling point of between 4090C, preferably 6090C.

The diazotising reaction is preferably carried out at a temperature below 30C. e.g. at 2025C., usually in hydrochloric acid having a concentration greater than lN, preferably between 5.5 and 6.5N. The reaction is also preferably carried out in the presence of acetic acid. The quantity of organic solvent is not critical but is preferably at least 20% by volume of the total reaction mixture, for example 2560% by volume.

The diazotisation reaction is generally continued for at least 2 but often less than 7 or even 5 hours. It is generally continued until there is substantially no solid material left suspended in the aqueous phase. The organic phase is then separated and is preferably evaporated to dryness before being hydrolysed. The hydrolysis may be carried out by reacting with a mineral acid, for ex- :ample concentrated hydrochloric acid, preferably in the presence of a water miscible solvent, for example methanol, ethanol or industrial methylated spirits. The

hydrolysis is suitably carried out at a temperature of 50-l50C. and preferably under reflux. The product can be isolated by conventional means and then, if desired, converted to benazolin; for example by the method described in British Pat. Specification No. 966,496. The method described in this specification comprises condensing the 4-chloro-2- hydroxybenzothiazole with a compound selected from ACH B or R OCH CN wherein A is a halogen atom, B is carboxyl group or the salt, ester, amide or nitrile thereof and R is an alkanesulphonyl or arylsulphonyl group, in the presence of an alkaline condensing agent to give a compound of formula I and if necessary converting B to give a desired group selected from carboxyl or the salts or esters thereof, such as those described above.

In addition to giving the advantage of producing high yields and faster reaction times than have been possible using solvents previously described, the use of the halo genated aliphatic hydrocarbons as solvents in the invention has a further important advantage. This is that the 2-amino-4-chlorobenzothiazole hydrohalide may be made by cyclising N-2-chlorophenylthiourea in the same organic solvent system as that used for the subsequent diazotisation reaction with the result that the 2-amino-4-ch]orobenzothiazole hydrohalide can be produced and reacted in the same organic solvent system without any necessity for isolating it before the diazotisation step. As a result of avoiding having to separate the compound before diazotisation the overall yield and the overall time required for carrying out the production of benazolin from N-2- chlorophenylthiourea is improved still further.

Preferred conditions for cyclising the N-2- chlorophenylthiourea to make 2-amino-4- chlorobenzothiazole hydrohalide comprise reacting the thiourea with a source of chlorine or bromine atoms in a halogenated aliphatic hydrocarbon solvent, such as those discussed above. The preferred source of chlorine atoms is sulphuryl chloride while the preferred source of bromine atoms is bromine. The reaction temperature is preferably 30 to 100C. The invention is illustrated in the following Examples in which percentages are by weight. The yields are of pure substance, so that the apparent yields (of impure material) are slightly higher than shown.

EXAMPLE 1 2-Amino-4-chlorobenzothiazole hydrobromide (79 g.) and ethylene dichloride (300 ml.) were added to a mixture of concentrated hydrochloric acid (114 ml.), glacial acetic acid (78 ml.) and water (l 14 ml.) in a 1 litre flask. The whole mixture was stirred and maintained at -25C. with water cooling whilst a solution of sodium nitrite (41 g.) in water (67 ml.) was added at a constant rate over 2 hours. The mixture was stirred for a further 2 hours. Water ml.) was added and the lower layer separated and evaporated to dryness. The residue was dissolved in hot industrial methylated spirits and the solution was maintained at a brisk reflux and stirred whilst concentrated hydrochloric acid 182 ml.) was added over 2 /2 hours. Stirring and heating were continued for a further 2 hours. The mixture was then cooled below 30C. and water (182 ml.) added. The solid was collected, washed free of acid and dried in vacuo at 60C. The 4-chloro-2- hydroxybenzothiazole so obtained was shown by titration with tetrabutylammonium hydroxide in acetone to have a purity of 95%. Yield 83% EXAMPLE 2 Example 1 was repeated replacing the ethylene dichloride with an equivalent volume of methylene chloride. The 4-chloro-2-hydroxybenzothiazole so obtained was shown to have a purity of 95%. Yield 87% EXAMPLE 3 N-2-chlorophenylthiourea (65 g.) was added to a mixture of glacial acetic acid (48 ml.) and ethylene dichloride (195 ml.) in a 1 litre flask. The mixture was stirred vigorously and bromine (61.5 g.) was added in one portion. When the temperature had stopped rising, the mixture was boiled under reflux for 4 hours. It was then cooled to between 15 and 20C. and a mixture of concentrated hydrochloric acid ml.) and water (1 15 ml.) was added. The temperature was maintained at 20 to 25C. whilst a solution of sodium nitrite (41 g.) in water was added over 2 hours. The experiment was then continued as in Example 1, to give 4-chloro-2- hydroxybenzothiazole which was shown to have a purity of 95%. Yield 83% EXAMPLE 4-9 Example 1 was repeated replacing the ethylene dichloride with in turn equivalent volumes of chloroform (Example 4); tetrachloroethylene (Example 5); 1,1,1- trichloroethane (Example 6); 1,2-dichloropropane (Example 7); ethylene dibromide (Example 8); and double the equivalent volume of carbon tetrachloride (Example 9). The 4-chloro-2-hydroxybenzothiazole obtained in each of these examples had a purity in the range 93 to 95% and gave yields of, respectively 73%, 66%, 65%, 72%, 61% and 71%. Higher yields may be obtained by conducting the diazotisation for a longer period.

EXAMPLE [0 A slurry of N-2-chlorophenylthiourea (65 g.) in a mixture of glacial acetic acid (48 mls.) and ethylene dichloride (36 ml.) was slowly added to a stirred solution of bromine (61.5 g.) in ethylene dichloride (97 ml.) whilst keeping the temperature below 55C with water cooling. .The mixture was carefully heated to reflux and maintained at that temperature for 4 hours. It was then cooled to between 15 and 20 C and the experiment continued as in Example 3 to give 4-chloro-2- hydroxybenzothiazole having a purity of 95%. Yield 84% EXAMPLE 1 l 4-Chloro-2-hydroxybenzothiazole (185.5 g.) obtained from Example 1 was mixed with anhydrous potassium carbonate (138.5 g.), sodium iodide (5 g.) and methyl ethyl ketone l L. The mixture was stirred and refluxed during the addition of ethyl chloroacetate (135 g.). The mixture was allowed to reflux for a further 4 hours, water (280 ml.) added and the mixture cooled to 70C. The aqueous layer was discarded and the organic layer evaporated to give an oil which was dissolved in refluxing industrial methylated spirits (200 ml.). Aqueous sodium hydroxide (2.5N; 440 ml.) was added and refluxing continued for one-half hour. The solution was then cooled and acidified to pH 1 to 2 with hydrochloric acid. The resulting product was filtered off, washed with water and dried to give benazolin, m.p. l858C.

EXAMPLE 12 In a similar manner to that described in Example 1 l, benazolin was obtained in turn from the 4-chloro-2- hydroxybenzothiazole prepared as in Examples 2 to 9.

COMPARATIVE EXAMPLE Example 1 was repeated except that benzene was used instead of ethylene dichloride, the sodium nitrite addition took 5 hours instead of 2 and the stirring was continued for 16 hours instead of 2 hours. The 4- chloro-2-hydroxybenzothiazole was obtained in 77% yield and was only 87% pure and was contaminated inter alia with 8.3% of 4-chloro-2-phenylbenzothiazole which was difficult to separate at this stage. When the product was converted into benazolin as described in Example 1 1 it was necessary to remove this impurity by carrying out an extraction with methylene chloride after the hydrolysis with sodium hydroxide.

I claim:

1. In a process for preparing 4-chloro-2- hydroxybenzothiazole which comprises diazotising 2-amino-4-chlorobenzothiazole hydrohalide in the presence of a solvent and hydrolysing the product, the improvement consisting of conducting the diazotisation in the presence of a halogenated aliphatic hydrocarbon solvent in which the major products of the diazotisation reaction are soluble to the extent of at least w/v at 20C, as said solvent.

2. A process according to claim 1 in which the solvent is a chlorinated hydrocarbon.

3. A process according to claim 1 in which the solvent is ethylene dichloride.

4. A process according to claim 1 in which the solvent is selected from methylene chloride, chloroform, carbon tetrachloride, tetrachlorethane, trichloroethylene, perchloroethylene, 1,l,l-trichloroethane and ethylene dibromide.

5. A process according to claim 1 in which the solution in halogenated aliphatic hydrocarbon solvent resulting from the diazotisation is separated from the reaction medium and is evaporated to dryness before the hydrolysis of the product.

6. A process according to claim 1 in which the 2-amino-4-chlorobenzothiazole is obtained by cyclising N-2-chlorophenylthiourea in the same solvent system as that used for the diazotisation reaction and is then subjected to the diazotisation without isolation from the solvent system.

7. A process according to claim 1 in which the 4- chloro-Z-hydroxybenzothiazole so obtained is condensed with a compound selected from ACH B and R OCI-l CN wherein A is a halogen atom, B is carboxyl group or the salt, ester, amide or nitrile thereof and R is an alkanesulphonyl or arylsulphonyl group, in the presence of an alkaline condensing agent to give a compound of formula I rrues I A U and if necessary converting B to give a desired group selected from carboxyl or the salt or ester thereof. 

1. IN A PROCESS FOR PREPARING 4-CHLORO-2HYDROXYBENZOTHIAZOLE WHICH COMPRISES DIAZOTISING 2-AMINO-4CHLOROBENZOTHIAZOLE HYDROHALIDE IN THE PRESENCE OF A SOLVENT AND HYDROLYSING THE PRODUCT, THE IMPROVEMENT CONSISTING OF CONDUCTING THE DIAZOTISATION IN THE PRESENCE OF A HALOGENATED ALIPHATIC HYDROCARBON SOLVENT IN WHICH THE MAJOR PRODUCTS OF THE DIAZOTISATION REACTION ARE SOLUBLE TO THE EXTENT OF AT LEAST 10% W/V AT 20*C, AS SAID SOLVENT.
 2. A process according to claim 1 in which the solvent is a chlorinated hydrocarbon.
 3. A process according to claim 1 in which the solvent is ethylene dichloride.
 4. A process according to claim 1 in which the solvent is selected from methylene chloride, chloroform, carbon tetrachloride, tetrachlorethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane and ethylene dibromide.
 5. A process according to claim 1 in which the solution in halogenated aliphatic hydrocarbon solvent resulting from the diazotisation is separated from the reaction medium and is evaporated to dryness before the hydrolysis of the product.
 6. A process according to claim 1 in which the 2-amino-4-chlorobenzothiazole is obtained by cyclising N-2-chlorophenylthiourea in the same solvent system as that used for the diazotisation reaction and is then subjected to the diazotisation without isolation from the solvent system.
 7. A process according to claim 1 in which the 4-chloro-2-hydroxybenzothiazole so obtained is condensed with a compound selected from ACH2B and R1OCH2CN wherein A is a halogen atom, B is carboxyl group or the salt, ester, amide or nitrile thereof and R1 is an alkanesulphonyl or arylsulphonyl group, in the presence of an alkaline condensing agent to give a compound of formula I 